Identification of novel amides and alkaloids as putative inhibitors of dopamine transporter for schizophrenia using computer-aided virtual screening

Schizophrenia is a complex psychiatric disorder marked by delusions, memory impairments, hallucinations, disorganized behavior, and severe cognitive deficits. Targeting the dopamine transporter (DAT) protein is promising for treating cognitive symptoms, especially in patients resistant to antipsychotic treatments. In this study, phytochemicals from six medicinal plants underwent virtual screening, and molecular dynamics simulation to identify potential agents targeting DAT. Key drug-like properties, safety, and biological activity were evaluated for identified hits. Pharmacokinetic simulation and pharmacophoric analysis were also performed. Among 990 screened phytochemicals, three alkaloids and six amides, predominantly from <i>Piper retrofractum,</i> and one diterpene were identified as potential antischizophrenic agents based on their stronger binding affinities and favorable docking scores compared to the standard (Lumateperone). Amides showed more potential for DAT than alkaloids. The dynamic behavior and stability of the top three amides, namely, Chenoalbicin, Dipiperamide G, and Lyciumamide C, were evaluated using various molecular dynamics analyses. RMSD (Root Mean Square Deviation), RMSF (Root Mean Square Fluctuation), Rg (Radius of Gyration), and SASA (Solvent Accessible Surface Area) analyses demonstrated favorable characteristics for all three ligands. However, binding free energy, cross-correlation, PCA (Principal Component Analysis) and FEL (Free Energy Landscape) analyses indicated that Lyciumamide C exhibited the highest stability and binding affinity in dynamic environments, Pharmacophoric features highlighted the distinct interacting components for the top three amides. Pharmacokinetic simulations revealed significant peak concentrations and sustained levels can be indicated as Lyciumamide C > Chenoalbicin > Dipiperamide G. The higher and more sustained brain concentrations of Lyciumamide C suggest its most promising pharmacokinetic profile for targeting DAT. Overall, our screened metabolites followed drug-ability criteria and require further experimental validation.